Artículos (Farmacología, Pediatría y Radiología)
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Artículo Prognostic significance of mutation type and chromosome fragility in Fanconi anemia(Wiley, 2024-11-19) Ramírez, María José; Pujol, Roser; Minguillón, Jordi; Bogliolo, Massimo; Persico, Ilaria; Cavero, Débora; Fernández-Teijeiro, Ana; Surrallés, Jordi; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Gobierno de España; Instituto de Salud Carlos III; European Union (UE); Generalitat de CatalunyaFanconi anemia (FA) is a rare genetic disease characterized by high phenotypic and genotypic heterogeneity, and extreme chromosome fragility. To better understand the natural history of FA, identify genetic risk and prognostic factors, and develop novel therapeutic strategies, the Spanish Registry of Patients with FA collects data on clinical features, chromosome fragility, genetic subtypes, and DNA sequencing with informed consent of participating individuals. In this article, we describe the clinical evolution of 227 patients followed up for up to 30 years, for whom our data indicate a cumulative cancer incidence of 86% by age 50. We found that patients with lower chromosome fragility had a milder malformation spectrum and better outcomes in terms of later-onset hematologic impairment, less severe bone marrow failure, and lower cancer risk. We also found that outcomes were better for patients with mutations leading to mutant FANCA protein expression (genetic hypomorphism) than for patients lacking this protein. Likewise, prognosis was consistently better for patients with biallelic mutations in FANCD2 (mainly hypomorphic mutations) than for patients with biallelic mutations in FANCA and FANCG, with the lack of the mutant protein in patients with biallelic mutations in FANCG contributing to their poorer outcomes. Our results regarding the clinical impact of chromosome fragility and genetic hypomorphism suggest that mutant FA proteins retain residual activity. This finding should encourage the development of novel therapeutic strategies aimed at partially or fully enhancing mutant FA function, thereby preventing or delaying bone marrow failure and cancer in patients with FA.Artículo Safety and efficacy of immunoguided prophylaxis for cytomegalovirus disease in low-risk lung transplant recipients in Spain: a multicentre, open-label, randomised, phase 3, noninferiority trial(Elsevier, 2025-03-26) Páez Vega, Aurora; Vaquero Barrios, José M.; Ruiz Arabi, Elisa; Iturbe Fernández, David; Alonso, Rodrigo; Ussetti Gil, Piedad; Lobo Acosta, María Ángeles; Gutiérrez Gutiérrez, Belén; Torre Cisneros, Julián; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red (CIBER); European Union (UE); Gobierno de España; Sociedad Andaluza de Trasplante de Órganos y Tejidos (SATOT)Background: The standard prophylaxis treatment for cytomegalovirus (CMV) disease in CMV-seropositive lung transplant recipients is six months of prophylaxis with valganciclovir followed by six months of pre-emptive therapy. This protocol is associated with adverse events and risk of resistance. We have previously shown that prophylaxis can be suspended in CMV-seropositive kidney transplant recipients receiving thymoglobulin without increasing the risk of CMV disease and reducing the incidence of neutropenia. The objective of the current study is to demonstrate that immunoguided prophylaxis is effective and safe in seropositive lung transplant recipients. Methods: A phase III, multicentre, randomised, open-label, noninferiority clinical trial was conducted in adult lung transplant recipients. Patients were randomised (1:1) to two groups: (1) immunoguided prophylaxis (IP), consisting of 3 months of universal prophylaxis followed by CMV-specific cell-mediated immunity-guided discontinuation, or (2) standard prophylaxis (SP), consisting of 6 months of prophylaxis followed by pre-emptive therapy, both for a total of 12 months. The noninferiority margin was 7%. The primary and secondary efficacy endpoints were CMV disease and asymptomatic CMV replication at month 18. The primary and secondary safety endpoints were incidence of neutropenia (defined as neutrophil count <1500 cells/μL), incidence of rejection and number of days of valganciclovir prophylaxis. This trial was registered in EudraCT (2018-003300-39) and ClinicalTrials.gov (NCT03699254). This trial has been completed. Findings: Patients were recruited between April 2019 and December 2021 in seven Spanish centres. A total of 150 patients were randomised (75 patients per group). Incidence of CMV disease at month 18 did not differ among groups (18·7% [14 patients] vs. 16·0% [12 patients]; risk difference [RD] −0·03 [95% CI −0·15% to 0·06%]; P = 0·620) but occurred earlier in the IP group compared to the SP group. The proportion of patients who developed CMV disease at ≤180 days after transplant was higher in the IP group compared with the SP group (8% [6 patients] vs. 0% [0 patients]; RD −0·08 [95% CI −0·14 to −0·02; P = 0·009]). Asymptomatic CMV replication was reduced in the IP group vs. the SP group (4·0% [3 patients] vs. 16·0% [12 patients]; adjusted RD 0·12 [95% CI 0·03–0·21; P = 0·009]). A total of 30 patients (40%) in the IP group did not require prophylaxis from month 4 to 12. No significant difference was observed in the proportion of patients with neutropenia during months 4 to 7 (14·7% [11 patients] vs. 25·3% [19 patients]; RD 0·11 [95% CI −0·02 to 0·23]; P = 0·090) or rejection (33·3% [25 patients] vs. 30·7% [23 patients]; RD −0·03 [95% CI −0·18 to 0·12; P = 0·690]). The median days of valganciclovir was lower in the IP group than in the SP group (137 [92–266] vs. 198 [173–281]; P < 0.001). Interpretation: Immunoguided prophylaxis was noninferior to the standard of care in preventing CMV disease in lung transplant recipients. It could be considered for implementing in clinical practice in CMV-seropositive lung transplant recipients upon considering the study limitations.Artículo Síndrome de Ondine. A propósito de un caso(Elsevier, 2023-10) León Carretero, Susana; Román Fernández, Ana; González Barreda, Carmen; Campo Barasoain, Andrea; Granero Asencio, Mercedes; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaRecién nacida a término, sin antecedentes prenatales de interés, ni factores de riesgo infeccioso. Presenta parto inducido por enfermedad materna con amniorrexis de 8 h de evolución que da lugar a líquido meconial espeso, finalizando mediante ventosa para abreviar expulsivo. Nace con test Apgar: 8/9/9 y pH cordón 7,34, precisando aspiración de secreciones, y ventilación con presión positiva intermitente en el primer minuto de vida, con evolución favorable, pero necesitando oxígeno suplementario para mantener adecuada saturación, por lo que ingresa en la Unidad Neonatal. (extracto)Artículo Síndrome tricorrinofalángico: un diagnóstico de visu al alcance del pediatra(Elsevier, 2023-12) Cortés Jiménez, María del Carmen; Fernández García, Raquel María; García García, Emilio José; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaEl síndrome tricorrinofalángico (TRPS) es una entidad poco frecuente de herencia autosómica dominante, alta penetrancia y expresividad variable, que se debe a una alteración en el gen TRPS1. Clínicamente se caracteriza por alteraciones del pelo (cabello escaso, adelgazamiento lateral de las cejas) y uñas (distrofia ungueal), leve dismorfia facial (punta nasal bulbosa, filtrum largo y plano, labio superior fino y pabellones auriculares prominentes) y anomalías esqueléticas (talla baja, braquidactilia, desviación de las falanges, epífisis de las falanges en forma de cono, displasia de caderas y osteopenia). Se subdivide en dos tipos: TRPS I (OMIM # 190350), que se debe a variantes patogénicas del gen TRPS1; y TRPS II (OMIM # 150230), que se produce por deleción de genes contiguos en el cromosoma 8 (incluyendo TRPS1 y EXT1) y asocia además osteocondromas y discapacidad intelectual. (extracto)Artículo Contrarréplica a la carta del Dr. Ramón Ugarte(Lúa Ediciones 3.0, 2024-06-04) Coronel Rodríguez, Cristóbal; Flores Méndez, Beatriz; Domínguez León, Victoria; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaAnte todo, agradecemos al Dr. Ramón Ugarte, experto en el tema, sus aportaciones e interés por nuestro estudio. Los datos indican que el uso de melatonina en los países desarrollados se está disparando en la última década sin control médico ni percepción por la sociedad de estar consumiendo una hormona, al estar comercializada como complemento alimenticio. Coincidimos con el Dr. Ramón Ugarte, en su carta publicada en febrero de 2024 en esta revista, en que a las casas comerciales le interesa que se hable de la melatonina, aunque sea para mal. Pero, como indica el actual coordinador del Grupo de Trabajo de Sueño de la Asociación Española de Pediatría de Atención Primaria (AEPap), el Dr. Ignacio Cruz, los pediatras españoles necesitamos estudios sobre la melatonina, sus dosis, sus indicaciones… Si los pediatras “miran hacia otro lado” y no hablan de melatonina, no por eso va a dejar de utilizarse y la información que no aporta la ciencia la dará cualquier otra fuente con otros intereses menos nobles. La melatonina se usa en España, ¿por qué si no iba a haber 53 presentaciones comerciales de una misma sustancia? La industria farmacéutica trabaja basándose en estudios de mercado, y esa cantidad pasmosa de productos ─con composición similar, al alcance del consumidor─ existe porque investigaciones comerciales habrán indicado que se van a vender y no hay ninguna regulación que lo impida. (extracto)Artículo ECLIM-SEHOP: how to develop a platform to conduct academic trials for childhood cancer(Springer, 2024-04-10) Juan Ribelles, Antonio; Bautista, Francisco; Cañete, Adela; Rubio San Simón, Alba; Alonso Saladrigues, Anna; Hladun, Raquel; Márquez Vega, Catalina; Fernández-Teijeiro, Ana; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; ACAYE, Uno entre cien mil; Asociación Española Contra el Cáncer (AECC); Asociación Pablo Ugarte; Federación Española de Padres de Niños con Cáncer; Fundación Inocente; Fundación MARIntroduction: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation. Methods: The platform’s database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted. Results: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months. Discussion: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.Artículo La dieta sin gluten cambia el perfil lipídico de los niños y adolescentes celíacos(Lúa Ediciones 3.0, 2024-10-10) Flores Méndez, Beatriz; Coronel Rodríguez, Cristóbal; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaIntroducción: la dieta sin gluten es el único tratamiento de la enfermedad celíaca. Los productos sin gluten contienen un mayor porcentaje de carbohidratos y lípidos saturados, lo que puede producir problemas metabólicos a largo plazo. Dado que la arteriosclerosis es la principal causa de morbimortalidad en los países desarrollados, el objetivo de este trabajo es analizar el perfil lipídico de niños y adolescentes por debajo de los 18 años tras su diagnóstico como celíacos y su modificación después de iniciar el tratamiento. Material y métodos: se llevó a cabo un estudio observacional retrospectivo de niños diagnosticados de enfermedad celíaca sin otra comorbilidad que seguían una dieta sin gluten estricta. Se recogieron y compararon los perfiles lipídicos al debut de la enfermedad, al año y a los 6 años del inicio de la dieta sin gluten. Resultados: en el estudio se incluyó a 24 pacientes pediátricos. Se objetivó un ascenso de los niveles de colesterol total y un descenso de los niveles de triglicéridos, ambos con significación estadística (p <0,05). Conclusiones: creemos importante analizar el perfil nutricional de los pacientes celíacos pediátricos al diagnóstico de la enfermedad, así como en el seguimiento de su dieta sin gluten, para poder detectar problemas metabólicos y/o nutricionales de manera precoz, atajando el desarrollo de consecuencias que pueden dar la cara ya desde el periodo infantil.Artículo Impact of pediatric inflammatory bowel disease on caregivers' work productivity: A multicenter study by the SEGHNP(Wiley, 2024-07-28) Velasco Rodríguez‐Belvís, Marta; Palomino, Laura; Pujol Muncunill, Gemma; Martin Masot, Rafael; Muñoz Codoceo, Rosa Ana; Barrio Torres, Josefa; Navas López, Víctor Manuel; Martín de Carpi, Javier; Millán Jiménez, Antonio; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaObjectives/Background: Pediatric inflammatory bowel disease (PIBD) poses significant challenges not only to patients but also to their families, particularly affecting the work productivity of caregivers. This Spanish multicenter study aims to elucidate the extent of this impact. Materials and Methods: A cross-sectional, multicenter study was conducted between February 2021 and June 2023, involving parents or caregivers of PIBD patients aged 10–18 years. The study utilized the Work Productivity and Activity Impairment (WPAI) questionnaires alongside assessing disease activity and socioeconomic status to quantify work productivity loss and its economic implications. Results: The study included 370 patients from 37 centers, highlighting a significant loss of work productivity among caregivers, especially mothers. The global unemployment rate was notably higher in this group compared to national averages (22.9% vs. 13.8%), particularly among females (30.7% vs. 13.7%), with absenteeism and presenteeism rates (26.4% and 39.9%) significantly impacting the caregivers' ability to work. The study also identified active disease and treatment with biologics or steroids as risk factors for increased work productivity loss. Conclusions: Caregivers of children with inflammatory bowel disease face considerable challenges in maintaining employment, with a notable economic impact due to lost work hours. The findings underscore the need for targeted support and interventions to assist these families, suggesting potential areas for policy improvement and support mechanisms to mitigate the socioeconomic burden of PIBD on affected families.Artículo Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature(Wiley, 2023-03-23) Gazdagh, Gabriella; Hunt, David; Cueto González, Anna María; Pons Rodríguez, Monserrat; Chaudhry, Ayeshah; Madruga, Marcos; González-Meneses López, Antonio; Baralle, Diana; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Agence Nationale de la Recherche; National Institute for Health and Care Research; National Institute for Health ResearchThe TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype-to-phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A > G (N1465S) and c.6244-2A > G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype-to-phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues.Artículo Generation of mesenchymal stromal cells from urine-derived iPSCs of pediatric brain tumor patients(Frontiers Media, 2023-01-26) Baliña Sánchez, Carmen; Aguilera, Yolanda; Adán, Norma; Sierra Párraga, Jesús María; Olmedo Moreno, Laura; Panadero Morón, Concepción; Cabello Laureano, Rosa; Márquez Vega, Catalina; Martín Montalvo, Alejandro; Capilla González, Vivian; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer (AECC); Junta de Andalucía; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Gobierno de EspañaHuman induced pluripotent stem cells (iPSCs) provide a virtually inexhaustible source of starting material for next generation cell therapies, offering new opportunities for regenerative medicine. Among different cell sources for the generation of iPSCs, urine cells are clinically relevant since these cells can be repeatedly obtained by non-invasive methods from patients of any age and health condition. These attributes encourage patients to participate in preclinical and clinical research. In particular, the use of urine-derived iPSC products is a convenient strategy for children with brain tumors, which are medically fragile patients. Here, we investigate the feasibility of using urine samples as a source of somatic cells to generate iPSC lines from pediatric patients with brain tumors (BT-iPSC). Urinary epithelial cells were isolated and reprogrammed using non-integrative Sendai virus vectors harboring the Yamanaka factors KLF4, OCT3/4, SOX2 and C-MYC. After reprogramming, BT-iPSC lines were subject to quality assessment and were compared to iPSCs obtained from urine samples of non-tumor pediatric patients (nonT-iPSC). We demonstrated that iPSCs can be successfully derived from a small volume of urine obtained from pediatric patients. Importantly, we showed that BT-iPSCs are equivalent to nonT-iPSCs in terms of morphology, pluripotency, and differentiation capacity into the three germ layers. In addition, both BT-iPSCs and nonT-iPSCs efficiently differentiated into functional mesenchymal stem/stromal cells (iMSC) with immunomodulatory properties. Therefore, this study provides an attractive approach to non-invasively generate personalized iMSC products intended for the treatment of children with brain tumors.Artículo Genetic diagnosis of Duchenne and Becker muscular dystrophy through mRNA analysis: new splicing events(Grupo editorial BMJ, 2022-12-19) Segarra Casas, Alba; Domínguez González, Cristina; Hernández Laín, Aurelio; Sánchez Calvin, María Teresa; Camacho, Ana; Rivas, Eloy; Campo Barasoain, Andrea; Gonzalez Quereda, Lidia; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Gobierno de EspañaBackground: Up to 7% of patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) remain genetically undiagnosed after routine genetic testing. These patients are thought to carry deep intronic variants, structural variants or splicing alterations not detected through multiplex ligation-dependent probe amplification or exome sequencing. Methods: RNA was extracted from seven muscle biopsy samples of patients with genetically undiagnosed DMD/BMD after routine genetic diagnosis. RT-PCR of the DMD gene was performed to detect the presence of alternative transcripts. Droplet digital PCR and whole-genome sequencing were also performed in some patients. Results: We identified an alteration in the mRNA level in all the patients. We detected three pseudoexons in DMD caused by deep intronic variants, two of them not previously reported. We also identified a chromosomal rearrangement between Xp21.2 and 8p22. Furthermore, we detected three exon skipping events with unclear pathogenicity. Conclusion: These findings indicate that mRNA analysis of the DMD gene is a valuable tool to reach a precise genetic diagnosis in patients with a clinical and anatomopathological suspicion of dystrophinopathy that remain genetically undiagnosed after routine genetic testing.Artículo Prevalencia, hábitos de consumo y complicaciones de los suplementos nutricionales proteicos en adolescentes(Elsevier, 2023-09-15) Millán Jiménez, Antonio; Fernández Fontán, Isabel María; Sobrino Toro, Manuel; Fernández Torres, Bartolomé; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. Departamento de CirugíaIntroducción: El consumo de suplementos nutricionales y proteicos por adolescentes puede tener importantes repercusiones para su salud. Material y método: Estudio prospectivo observacional, basado en una encuesta, dirigido a los adolescentes de seis colegios, seleccionados aleatoriamente, de la ciudad de Sevilla. Nuestro objetivo principal es conocer el consumo real de suplementos alimentarios entre la población adolescente, cuantificando su contenido proteico. Resultados: Se obtuvieron 263 respuestas válidas, objetivando una prevalencia de consumo de 19,01% para todos los suplementos nutricionales, de ellos 56,0% tomaban suplementos de proteínas (10,64% del total), con una ingesta media de estas últimas de 0,26 ± 0,18 g/kg/día. El perfil del consumidor de cualquier tipo de suplementos se diferencia del de los que no los utilizan en la edad, el uso de medicación habitual y realizar dieta para perder peso o hiperproteica. Al comparar los adolescentes que ingerían productos proteicos con los no proteicos, la única variación significativa estuvo en el control del consumo. Aunque la mayoría no tiene control externo, en 25,92% de los que tomaban proteínas el seguimiento lo hacía un profesional, vs. 7,38% de los que ingerían suplementos no proteicos. De los consumidores de productos proteicos, 85,18% consiguió el objetivo buscado y 18,51% refirió algún efecto negativo. Conclusiones: La prevalencia de consumo de suplementos proteicos entre los adolescentes de nuestro medio es del 10,64%, en cantidades que suponen un 25% de las proteínas que deben ingerir diariamente. El perfil de consumidor de suplementos proteicos es muy similar al de aquel que toma productos no proteicos.Artículo Characterization of Rugulopteryx okamurae algae: A source of bioactive peptides, omega-3 fatty acids, and volatile compounds(Elsevier, 2025-05-01) Rivero Pino, Fernando; González de la Rosa, Teresa; Torrecillas López, María; Barrera Chamorro, Luna; Río-Vázquez, José Luis del; Márquez Parada, Elvira; Fernández Prior, África; Garcáa-Vaquero, Marco; García Gómez, José Carlos; Montserrat de la Paz, Sergio; Claro Cala, Carmen María; Universidad de Sevilla. Departamento de Zoología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaThis study provides a detailed characterization of the invasive algae Rugulopteryx okamurae, highlighting its nutritional composition, mineral content, and potential bioactive compounds. This biomass contains 14.18 % protein, 21.29 % lipids (with a high omega-3 content), fibre (31.32 %), and significant amounts of minerals like calcium, sodium, potassium, sulphur, and iron. Phenolic compounds (0.74 %) and volatile compounds, such as retinol, were also identified. Peptidome analysis revealed 626 unique peptides, with 21 low molecular weight peptides showing potential activity against angiotensin converting enzyme and dipeptidyl peptidase IV when assessed using in silico tools and using molecular docking. Additionally, the antioxidant capacity of the alga was demonstrated with a significant free radical inhibition (EC50: 2.09 mg/mL). Overall, this study provides initial evidence on the nutritional potential of R. okamurae, which may have potential for future applications in food and biotechnology fields.Artículo Recent Evidence-Based Clinical Guide for the Use of Dinutuximab Beta in Pediatric Patients with Neuroblastoma(Springer Adis, 2022-12-12) Balaguer, Julia; García Hidalgo, Laura; Hladun, Raquel; Márquez Vega, Catalina; Pérez Alonso, Vanesa; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaThe anti-GD2 antibody dinutuximab beta (Qarziba®) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive results obtained in different studies. In both the first-line and relapsed/refractory settings, treatment with dinutuximab beta attains objective clinical responses in children with high-risk neuroblastoma. Its incorporation has changed the outcome for these patients and optimized management should be guaranteed to minimize possible adverse effects. Most prevalent adverse events include pain, allergic reactions, fever and capillary leak syndrome. There are still no evidence-based clinical guidelines that include the latest published evidence to optimize its use, as it depends on the experience gained in each referral center. Topics such as the mode of preparation and administration, the concomitant use of interleukin-2, the recommended pediatric age and dose for its use, or the adequate management of possible toxicities are important aspects to review. The objective of this article was to update the clinical guide to management with dinutuximab beta of children with neuroblastoma based on the most recent published evidence and our own experience in clinical practice.Artículo Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study(Elsevier, 2023-03) Mauz-Körholz, Christine; Landman Parker, Judith; Fernández-Teijeiro, Ana; Attarbaschi, Andishe; Balwierz, Walentyna; Bartelt, Jörg Martin; Kluge, Regine; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaBackground: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. Methods: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1–5; prednisone 60 mg/m2 orally on days 1–15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006–000995-33) and is completed. Findings: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1–69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3–89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8–92·5), for which the 95% CI included the 90% target rate. The most common grade 3–4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. Interpretation: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment.Artículo Long-term efficacy and safety of vestronidase alfa enzyme replacement therapy in pediatric subjects < 5 years with mucopolysaccharidosis VII(Elsevier, 2023-03-09) Lau, Heather A.; Viskochil, David; Tanpaiboon, Pranoot; González-Meneses López, Antonio; Martins, Esmeralda; Taylor, Julie; Malkus, Betsy; Zhang, Lin; Jurecka, Agnieszka; Marsden, Deborah; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaMucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). β-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment. An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human β-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period). The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of −60% (6.6) at week 4 (first post-baseline assessment) and −61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean [standard deviation] at baseline, −2.630 [1.17], n = 8; at week 48, −2.045 [0.27], n = 7) and growth velocity (mean [SD] Z-score at baseline, −2.59 [1.49], n = 4; at week 48, −0.39 [2.10], n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects. In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age.Artículo Mediterranean Diet and its Effects on Silent Brain Infarcts in a Cohort of Patients With Atrial Fibrillation(SAGE Publications, 2022-11-11) Escudero Martínez, Irene María; Mancha, Fernando; Vega, Ángela; Zapata, Montserrat; Ocete Pérez, Rafael F.; Álvarez, Lucía; Montaner, Joan; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaBackground and Aims: The benefits of Mediterranean Diet (MeDiet) in prevention of cardiovascular diseases (CVD) in general and ischemic stroke (IS) have been extensively studied and reported. We hypothesize that the consumption of nutrients typical of MeDiet would also reduce the rate of silent brain infarcts (SBI) among AF patients. Methods and Results: Patients with a history of AF who scored 0 to 1 in the CHADS2 score, ⩾50 years and with absence of neurological symptoms were selected from Seville urban area using the Andalusian electronic healthcare database. A 3T brain MRI was performed to all participants. Demographic and clinical data and food-frequency questionnaire (FFQ) were collected. Of the 443 scanned patients, 66 presented SBI. Of them 52 accepted to be scheduled for a clinical visit and were included in the diet sub study and 41 controls were matched per age and sex. There were no statistically significant differences in baseline characteristics. After logistic regression analysis, we found that a higher consumption of fiber from fruit was independently associated with a lower risk of SBI, while a higher consumption of high glycemic load (GL) foods was associated with a higher risk of SBI in a population with AF Conclusion: Our findings support that MeDiet could be suggested as a prevention strategy for SBI in patients with AF.Artículo Papel de la proteína asociada a pancreatitis en el cribado neonatal de la fibrosis quística(Asociación de Neumología y Cirugía Torácica del Sur (Neumosur), 2022-06-23) Delgado Pecellín, Isabel; Quintana-Gallego, Esther; Mora Vallellano, Josefa; López-Campos Bodineau, José Luis; Álvarez Ríos, Ana Isabel; Moreno Valera, José; Delgado Pecellín, Carmen; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. Departamento de MedicinaObjetivo: El objetivo es comparar la eficacia de dos métodos de cribado de fibrosis quística (FQ) mediante la utilización de la medición del tripsinógeno inmunorreactivo (TIR) y la proteína asociada pancreatitis (PAP) en gota de sangre seca. Métodos: Estudio observacional prospectivo que evaluó a neonatos con niveles de TIR inicial (TIR1) mayor de 50ng/mL a los que se le ha realizado cuantificación de la PAP y una segunda determinación de TIR (TIR2) entre diciembre 2017 y junio 2020. Se comparó la detección de FQ entre dos protocolos de cribado TIR1/ TIR2 vs TIR1/PAP/TIR2. Resultados: Durante el período analizado se sometieron a cribado neonatal 60.399 neonatos, de los que 316 tuvieron TIR1 elevada. Se confirmaron 10 casos de FQ, con una incidencia de 1 caso por cada 6.039 neonatos cribados. El protocolo TIR1/TIR2 identificó 34 casos con una sensibilidad del 88,89%, especificidad 91,53%, valor predictivo positivo 23,53% y valor predictivo negativo de 99,65%. El protocolo TIR1/PAP/TIR2 obtuvo una sensibilidad 88,89 %, especificidad 96,42%, valor predictivo positivo 42,11% y valor predictivo negativo 99,66%. El alelo c.1521_1523delCTT se identificó en el 80% de los casos. Conclusiones: El protocolo TIR1/PAP/TIR2 aumenta la especificidad del cribado neonatal, obteniendo una disminución del 4,89% de la proporción de falsos positivos respecto al protocolo TIR1/TIR2. Este nuevo protocolo de cribado puede permitir hacer un cribado de la FQ más eficiente.Artículo Genotype–phenotype correlation of 17 cases of Pompe disease in Spanish patients and identification of 4 novel GAA variants(BioMed Central, 2021-05-21) Hernández Arévalo, Paula; Santotoribio, José D.; Delarosa Rodríguez, Rocío; González-Meneses López, Antonio; García Morillo, Salvador; Jiménez Arriscado, Pilar; Guerrero Montávez, Juan Miguel; Macher, Hada C.; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI); European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)Background: Pompe disease (PD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the acid α-glucosidase gene (GAA) that produces defects in the lysosomal acid α-1,4-glucosidase. We aimed to identify genetic variations and clinical features in Spanish subjects to establish genotype–phenotype correlation. Methods: A total of 2637 samples of patients who showed symptoms or susceptible signs of PD were enrolled in this observational study. Enzymatic activity was detected by fluorometric techniques and the genetic study was carried out using Next-Generation Sequencing. Results: Fourteen different variants from 17 diagnosed patients were identified, seven males and nine females with LOPD (mean age 36.07, SD 20.57, range 7–64) and a 2-day-old boy with IOPD, four genetic variants had not been described in the literature previously, including a homozygous variant. In all of them α-glucosidase activity was decreased. Muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia and myalgia were commonly observed in patients. Conclusions: This study report four new genetic variants that contribute to the pathogenic variants spectrum of the GAA gene. We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T>G being the most prevalent variant. Furthermore, it was confirmed that the c.236_246delCCACACAGTGC pathogenic variant in homozygosity is associated with early disease and a worse prognosis.Artículo Open-label phase 1/2 study of vestronidase alfa for mucopolysaccharidosis VII(Elsevier, 2021-05-29) Jones, Simon; Coker, Mahmut; González-Meneses López, Antonio; Sniadecki, Jennifer; Mayhew, Jill; Hensman, Pauline; Jurecka, Agnieszka; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaVestronidase alfa is an enzyme replacement therapy for mucopolysaccharidosis VII (MPS VII). In this open-label, phase 1/2 study, three subjects with MPS VII received intravenous vestronidase alfa administered every other week (QOW) for 14 weeks (2 mg/kg), followed by 24-week forced-dose titration (1, 4, and 2 mg/kg QOW; 8 weeks each), 36-week continuation (2 mg/kg), and long-term extension (4 mg/kg). Vestronidase alfa was well tolerated and led to dose-responsive, sustained reductions in urinary glycosaminoglycan excretion.